Summary

The goal of this clinical research study is to find the highest tolerable dose of a
combination of dasatinib, cetuximab and FOLFOX (5-fluorouracil [5-FU], leucovorin [LV], and
Eloxatin [oxaliplatin]) that can be given to patients with metastatic colorectal cancer.
The safety of these drugs in combination will also be studied.

Description

Cetuximab is a drug designed to block the activity of EGFR, a protein on the surface of some
tumor cells that may cause the cells to grow. Blocking EGFR may stop or slow the growth of
tumor cells. Dasatinib is a drug that inhibits a protein called c-Src. High levels of
c-Src may make it harder for chemotherapy to work against the cancer. If dasatinib can
inhibit c-Src, the chemotherapy may be more effective against the cancer. FOLFOX is a drug
combination frequently used to treat colon or rectal cancer that has spread to other parts
of the body. FOLFOX is designed to kill rapidly dividing cells by preventing DNA (the
genetic material of cells) from duplicating.

Before you can start taking the drugs on this study, you will have what are called
"screening tests." These tests will help the doctor decide if you are eligible to take part
in this study. Your complete medical history will be recorded, and you will be asked about
any drugs you may be taking or have taken in the past. You will have a physical exam,
including measurement of your vital signs (heart rate, temperature, breathing rate, and
blood pressure), height, and weight. You will be asked how well you are able to perform the
normal activities of daily living (a performance status evaluation). You will have an
electrocardiogram (ECG - a test that measures the electrical activity of the heart). You
will have a chest x-ray and either a computed tomography (CT) or magnetic resonance imaging
(MRI) scan of your abdomen (stomach area) and pelvis to check the status of the disease.
X-rays, CT scans, or MRIs may be taken of other areas of your body if your doctor thinks it
is necessary. Blood (about 1-2 tablespoons) will be drawn for routine tests. This routine
blood draw will include a pregnancy test for women who are able to have children. To be
eligible to take part in this study, the pregnancy test must be negative.

Tumor tissue from a previous biopsy or surgery will be used to test a gene called KRAS.
Recent studies have found that cetuximab, when given alone or in combination with other
chemotherapy drugs, was not effective when given to patients with colorectal cancer that had
a mutation of a certain type of gene called KRAS. If you have the KRAS gene mutation, you
will not take part in this study.

If you are found to be eligible to take part in this study, you will begin receiving the
study drugs at a dose based on when you join the study. Three (3) to 6 participants will be
entered at each dose level. Each new group of participants will receive a higher dose, until
the highest tolerable dose is found. Once the highest tolerable dose is found, 12
participants will be enrolled at that dose level. Your doctor will tell you what dose level
you will be receiving and how this dose compares to the doses other participants have
received. The starting dose of cetuximab and FOLFOX will be the same for all participants.
The dose of dasatinib will be increased with the next group of 3-6 participants. Every 14
days is considered 1 study "cycle".

If you are enrolled at the highest tolerable dose level, you will have 2 core liver
biopsies. The liver tissue will be studied to learn the effect of the study drugs on
stopping the protein c-Src. You will have 2 liver biopsies collected. The first liver
biopsy will be collected before you start the study drugs, and the second will be performed
in either Cycle 2 or 3. Before the liver biopsy, you will receive fluids and drugs for
relaxation and/or pain through an needle in your arm or hand. You will be awake during the
biopsy. A radiologist will find the tumor in the liver with the help of radiographic
imaging procedures such as an ultrasound or CT scan. Your skin around this area will be
cleansed, and a local anesthetic will be given. A long, hollow needle will be inserted
through the skin into the liver tumor, and a tissue sample(s) will be taken.

Before receiving the study drugs, you will have a central venous catheter (CVC) placed. A
CVC is a sterile flexible tube that will be placed into a large vein while you are under
local anesthesia. Your doctor will explain this procedure to you in more detail, and you
will be required to sign a separate consent form for this procedure.

You will take dasatinib by mouth once a day, everyday during this study. Your study doctor
and research nurse will tell you how many pills you will take. Dasatinib should be taken
at the same time each day, with or without meals. If you miss a dose of dasatinib, you
should not double the next dose. It is important to take dasatinib with water, and not fruit
juices. You should not drink grapefruit juice or eat grapefruit while you are on this
study. Dasatinib should not be touched by children, pregnant women, or women who are
breastfeeding. If a caregiver must handle the drug, a protective glove should be worn.

While you are taking dasatinib, you will be given a drug diary. In this diary, you will
write down the date, the time, and the number of dasatinib tablets taken. Certain drugs and
herbal supplements may not be taken while you are receiving dasatinib. These drugs could
affect how your body breaks down dasatinib, which could have a bad effect on you. Your
doctor will give you a list of drugs and herbal supplements that you must not take while on
this study. You must tell your doctor before taking any new drugs while on this study.

On Day 1 of every cycle, you will receive oxaliplatin and LV through the CVC over about 2
hours. On Day 1, you will receive 5-FU through the CVC over less than 5 minutes. You will
then receive 5-FU through a portable pump for the next 46 hours. On Days 1 and 8, you will
receive cetuximab through the CVC over about 2 hours.

On Day 8, blood (about 1-2 tablespoons) will be drawn for routine tests.

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study
drugs and on Day 8 of Cycles 2 and 4. This blood will be drawn at the same time as your
routine blood tests are drawn. These blood samples will be used to develop tests that may
help doctors be able to predict who will best benefit from dasatinib.

If you are enrolled in the group that receives the highest tolerable dose level, the Day 8
blood draw during cycle 2 will not be performed. Instead, blood will be collected at the
time of the liver biopsy that is to be performed between Days 8-14 of cycle 2 or 3 about 2
to 6 hours after taking the daily dose of dasatinib.

Before each new cycle, you will be asked questions about any side effects you may have had.
At each visit, it is important to tell the study staff about any drugs you are currently
taking. You will have a physical exam, including measurement of your vital signs. You will
have a performance status evaluation. Blood (about 1-2 tablespoons) will be drawn for
routine tests.

You will also have either CT scans or MRIs of the tumor(s) every 8 weeks. Additional tests
may be done during this study, if your study doctor thinks it is necessary.

If you experience severe side effects, the study drugs may be delayed, stopped, or you may
receive smaller doses of the drugs.

You may remain on this study for as long as you are benefiting. You will be taken off this
study if the disease gets worse or intolerable side effects occur.

Once you are off-study, you will have an end-of-study visit. At this visit, blood (about 3
tablespoons) and urine will be collected for routine tests. You will have a physical exam.
You will have a CT scan or MRI scan of your abdomen and pelvis to check the status of the
disease. If you are having side effects after you stop receiving the study drugs, you will
be contacted by phone to check how you are feeling, or you will have follow-up visits until
the side effects have gone away.

This is an investigational study. Dasatinib is FDA approved for the treatment of leukemia.
Its use in this study, for this disease, is considered to be investigational. Cetuximab,
5-FU, LV, and oxaliplatin are all FDA approved and commercially available for the treatment
of colorectal cancer. Up to 42 patients will take part in this study. All patients will be
enrolled at M. D. Anderson.

Adjuvant chemotherapy for colorectal cancer is mainly based on the combination of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX-4). The pharmacological target of oxaliplatin remains intracellul...

The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafu...

The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been d...

Medical and Biotech [MESH] Definitions

Colorectal Neoplasms

Tumors or cancer of the COLON or the RECTUM or both. Risk factors for colorectal cancer include chronic ULCERATIVE COLITIS; FAMILIAL POLYPOSIS COLI; exposure to ASBESTOS; and irradiation of the CERVIX UTERI.

Genes, Mcc

Tumor suppressor genes located in the 5q21 region on the long arm of human chromosome 5. The mutation of these genes is associated with the formation of colorectal cancer (MCC stands for mutated in colorectal cancer).

Genes, Dcc

Tumor suppressor genes located in the 18q21-qter region of human chromosome 18. The absence of these genes is associated with the formation of colorectal cancer (DCC stands for deleted in colorectal cancer). The products of these genes show significant homology to neural cell adhesion molecules and other related cell surface glycoproteins.

Colorectal Neoplasms, Hereditary Nonpolyposis

A group of autosomal-dominant inherited diseases in which COLON CANCER arises in discrete adenomas. Unlike FAMILIAL POLYPOSIS COLI with hundreds of polyps, hereditary nonpolyposis colorectal neoplasms occur much later, in the fourth and fifth decades. HNPCC has been associated with germline mutations in mismatch repair (MMR) genes. It has been subdivided into Lynch syndrome I or site-specific colonic cancer, and LYNCH SYNDROME II which includes extracolonic cancer.

Tumor Suppressor Protein P53

Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.

Relevant Topics

PharmacyPharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs.
The scope of...

NutritionWithin medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...